Laryngotracheoesophageal Cleft Type IV in a Preterm Neonate. A Case Report and Literature Review.

We present a case of a preterm neonate with a type IV laryngo-tracheo-oesophageal cleft, an uncommon congenital malformation, resulting from the failure of separation of the trachea and the oesophagus during fetal development, often associated with other deformities as well. Data in the literature shows that the long-term morbidity from the entity has declined over the last decades, even though prognosis remains unfavourable for types III and IV. This report emphasizes the complex issues neonatologists are faced with, when treating neonates with this rare disorder in the first days of life, what will raise suspicion of this rare medical entity, and that direct laryngoscopy/bronchoscopy finally depicts the exact extension of the medical condition. At the same time extensive evaluation for coexisting congenital anomalies should be performed. For all the above reasons, these neonates should be treated in specialized tertiary pediatric centers for multidisciplinary prompt management, which may improve, the outcome.

Gut microbiome and attention deficit/hyperactivity disorder: a systematic review.

BACKROUND: This systematic review aims to examine the associations between features of gut microbiome and Attention Deficit/Hyperactivity Disorder (ADHD) risk or severity in children, adolescents and young adults. METHODS: Eligible studies were identified in PubMed and Google Scholar databases until December 31, 2020. RESULTS: The search identified a total of 1197 items, of which 11 were included in this systematic review. The findings regarding alpha, beta diversity, bacterial phyla, orders and families were inconclusive. At the genus level an increased abundance of Odoribacter (two studies) and Eggerthella (two studies) was found in ADHD; on the contrary, decreased abundance of Faecalibacterium (three studies) was noted, whereas one study suggested its inverse association with ADHD severity and hyperactivity. One study indicated that Bacteroides species also correlated with levels of hyperactivity and impulsivity. At the species level, a lower abundance of Faecalibacterium prausnitzii, but higher of Odoribacter splanchnicus and Bacteroides uniformis was reported. CONCLUSIONS: This systematic review highlights associations between gut microbiome features and ADHD. Potential mechanisms differ by microorganism and include effects on neurotransmitter production, dopamine metabolism, modulation of inflammation and neurodevelopment through the release of cytokines. IMPACT: The existence of correlations between features of gut microbiome and ADHD manifestation or its severity in children, adolescents and young adults. Associations between gut microbiome features and ADHD are highlighted. Potential mechanisms seem to differ by microorganism and include effects on neurotransmitter production, dopamine metabolism, modulation of inflammation and neurodevelopment through the release of cytokines. As correlations between gut microbiome features and ADHD seem to exist, additional studies are needed for further investigation.

Economic evaluation in psychiatric pharmacogenomics: a systematic review.

Nowadays, many relevant drug-gene associations have been discovered, but pharmacogenomics (PGx)-guided treatment needs to be cost-effective as well as clinically beneficial to be incorporated into standard health care. To address current challenges, this systematic review provides an update regarding previously published studies, which assessed the cost-effectiveness of PGx testing for the prescription of antidepressants and antipsychotics. From a total of 1159 studies initially identified by literature database querying, and after manual assessment and curation of all of them, a mere 18 studies met our inclusion criteria. Of the 18 studies evaluations, 16 studies (88.89%) drew conclusions in favor of PGx testing, of which 9 (50%) genome-guided interventions were cost-effective and 7 (38.9%) were less costly compared to standard treatment based on cost analysis. More precisely, supportive evidence exists for CYP2D6 and CYP2C19 drug-gene associations and for combinatorial PGx panels, but evidence is limited for many other drug-gene combinations. Amongst the limitations of the field are the unclear explanation of perspective and cost inputs, as well as the underreporting of study design elements, which can influence though the economic evaluation. Overall, the findings of this article demonstrate that although there is growing evidence on the cost-effectiveness of genome-guided interventions in psychiatric diseases, there is still a need for performing additional research on economic evaluations of PGx implementation with an emphasis on psychiatric disorders.

New molecular diagnostic trends and biomarkers for amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a rare and fatal neurodegenerative disorder. Two forms are recognized, familial (FALS) that accounts for 5-10% of ALS cases, and sporadic (SALS) that accounts for the rest. Early diagnosis of ALS is important because it improves their therapeutic efficacy. Current diagnosis is based on clinical assessment and requires approximately 12 months, leading to a significant delay in drug administration. Therefore, new methods are required for the earlier diagnosis of ALS. Screening for pathogenic variants in known ALS-associated genes is already exploited as a diagnostic tool in ALS but cannot be applied for population-based screening. New circulating biomarkers (proteins or small molecules) are needed for initial screening, whereas specific diagnostic methods can be applied to confirm the presence of pathogenic variants in the selected population subgroup. Lipids appear as promising biomarkers for population-based screening and for monitoring disease progression. Genetic analysis can also assist in the prediction of disease progression by analyzing disease-modifying genes, for example, EPHA4 and CHGB. Furthermore, molecular diagnosis will aid the stratification of ALS patients for improved pharmacological approaches. Here, we discuss current and novel diagnostic strategies and how they can be applied to revolutionize the field of ALS molecular diagnosis.

Genomic variants in the FTO gene are associated with sporadic amyotrophic lateral sclerosis in Greek patients.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating disease whose complex pathology has been associated with a strong genetic component in the context of both familial and sporadic disease. Herein, we adopted a next-generation sequencing approach to Greek patients suffering from sporadic ALS (together with their healthy counterparts) in order to explore further the genetic basis of sporadic ALS (sALS). RESULTS: Whole-genome sequencing analysis of Greek sALS patients revealed a positive association between FTO and TBC1D1 gene variants and sALS. Further, linkage disequilibrium analyses were suggestive of a specific disease-associated haplotype for FTO gene variants. Genotyping for these variants was performed in Greek, Sardinian, and Turkish sALS patients. A lack of association between FTO and TBC1D1 variants and sALS in patients of Sardinian and Turkish descent may suggest a founder effect in the Greek population. FTO was found to be highly expressed in motor neurons, while in silico analyses predicted an impact on FTO and TBC1D1 mRNA splicing for the genomic variants in question. CONCLUSIONS: To our knowledge, this is the first study to present a possible association between FTO gene variants and the genetic etiology of sALS. In addition, the next-generation sequencing-based genomics approach coupled with the two-step validation strategy described herein has the potential to be applied to other types of human complex genetic disorders in order to identify variants of clinical significance.

Success stories in genomic medicine from resource-limited countries.

In recent years, the translation of genomic discoveries into mainstream medical practice and public health has gained momentum, facilitated by the advent of new technologies. However, there are often major discrepancies in the pace of implementation of genomic medicine between developed and developing/resource-limited countries. The main reason does not only lie in the limitation of resources but also in the slow pace of adoption of the new findings and the poor understanding of the potential that this new discipline offers to rationalize medical diagnosis and treatment. Here, we present and critically discuss examples from the successful implementation of genomic medicine in resource-limited countries, focusing on pharmacogenomics, genome informatics, and public health genomics, emphasizing in the latter case genomic education, stakeholder analysis, and economics in pharmacogenomics. These examples can be considered as model cases and be readily replicated for the wide implementation of pharmacogenomics and genomic medicine in other resource-limited environments.

Identification of cancer predisposition variants in apparently healthy individuals using a next-generation sequencing-based family genomics approach.

Cancer, like many common disorders, has a complex etiology, often with a strong genetic component and with multiple environmental factors contributing to susceptibility. A considerable number of genomic variants have been previously reported to be causative of, or associated with, an increased risk for various types of cancer. Here, we adopted a next-generation sequencing approach in 11 members of two families of Greek descent to identify all genomic variants with the potential to predispose family members to cancer. Cross-comparison with data from the Human Gene Mutation Database identified a total of 571 variants, from which 47 % were disease-associated polymorphisms, 26 % disease-associated polymorphisms with additional supporting functional evidence, 19 % functional polymorphisms with in vitro/laboratory or in vivo supporting evidence but no known disease association, 4 % putative disease-causing mutations but with some residual doubt as to their pathological significance, and 3 % disease-causing mutations. Subsequent analysis, focused on the latter variant class most likely to be involved in cancer predisposition, revealed two variants of prime interest, namely MSH2 c.2732T>A (p.L911R) and BRCA1 c.2955delC, the first of which is novel. KMT2D c.13895delC and c.1940C>A variants are additionally reported as incidental findings. The next-generation sequencing-based family genomics approach described herein has the potential to be applied to other types of complex genetic disorder in order to identify variants of potential pathological significance.

Novel Pathogenic Variants Leading to Sporadic Amyotrophic Lateral Sclerosis in Greek Patients.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive disease that affects motor neurons, leading to paralysis and death usually 3-5 years after the onset of symptoms. The investigation of both sporadic and familial ALS highlighted four main genes that contribute to the pathogenesis of the disease: SOD1, FUS, TARDBP and C9orf72. This study aims to provide a comprehensive investigation of genetic variants found in SOD1, FUS and TARDBP genes in Greek sporadic ALS (sALS) cases. Our sequencing analysis of the coding regions of the abovementioned genes that include the majority of the variants that lead to ALS in 32 sALS patients and 3 healthy relatives revealed 6 variants in SOD1, 19 variants in FUS and 37 variants in TARDBP, of which the SOD1 p.D90A and the FUS c.*356G>A (rs886051940) variants have been previously associated with ALS, while two novel nonsense pathogenic variants were also identified, namely FUS p.R241* and TDP-43 p.Y214*. Our study contributes to the worldwide effort toward clarifying the genetic basis of sALS to better understand the disease's molecular pathology.

Congenital Diaphragmatic Eventration in the Neonatal Period: Systematic Review of the Literature and Report of a Rare Case Presenting with Gastrointestinal Disorders.

BACKGROUND: The term congenital diaphragmatic eventration (CDE) refers to an anatomical abnormality of the diaphragm. It is a very rare condition; however, early and prompt diagnosis is of very great importance due to possible life-threatening complications. Most severely affected patients are neonates, usually presented with respiratory distress symptoms. The aim of this study was to systematically review the existing literature and to consolidate data on CDE in neonates as well as to report a case of a neonate with congenital diaphragmatic eventration of the left hemidiaphragm and clinical signs and symptoms of the gastrointestinal tract. METHODS: An electronic search of the PubMed and Scopus databases was performed regarding studies evaluating the clinical presentation, diagnosis methods, treatments, and outcomes of CDE in the neonatal population. RESULTS: Data from 93 studies were integrated into our review, reporting 204 CDE cases, and according to them, the male/female ratio was 1/1 with a predominance of right-sided eventration. The diagnosis was primarily established by chest X-ray; surgical intervention was the most frequent treatment. The recurrence rate was 8.3% (9/109 cases). CONCLUSIONS: Early and accurate diagnosis of CDE and repair of the diaphragm can prevent complications, reduce morbidity, and improve the quality of patient's life.

The Festival of Genetics and Personalized Medicine.

Implementation of personalized medicine in the clinic is a lengthy and multifaceted approach that is also dependent on the raising of the general public's awareness of genomics. The Festival of Genetics and Personalized Medicine aims to familiarize the general public with the principles and applications of genetics and personalized medicine using numerous approaches - namely, a theatrical performance; a roundtable discussion of emerging topics in the field, such as pharmacogenomics, clinical genetics, bioinformatics, bioethics and health economics; the 'Genome: Unlocking Life's Code' exhibition, with its do-it-yourself format; and a live demonstration of 2MoBiL, a portable molecular biology laboratory. This festival attracted more than 900 participants and helped disseminate to a broader audience the principles of genetics and personalized medicine.

Inference Control in a Diabetes Data Set Using a Java-Based Prototype of LDH Algorithm.

Data sharing among different entities in the healthcare domain has become an increasingly common practice, where each entity would most likely want to prevent indirect data disclosure via inference channels. The Local Distortion Hiding (LDH) algorithm has been developed to protect sensitive decision tree (DT) rules, which are chosen not to be disclosed when DT construction techniques are applied to the data. This article presents eight experiments using a Java-based prototype that implements the LDH algorithm in a diabetes data set. Our experiments test the ability of the LDH algorithm in two ways, firstly in inference control and secondly in maintaining the structure and the performance metrics of the resulting DT. Our experiments on hiding eight terminal nodes in a diabetes data set using a Java-based prototype that implements the LDH algorithm, yield satisfactory results.

Relevance of pharmacogenomics for developing countries in Europe.

Pharmacogenomics holds promise of personalized treatment for patients suffering from many common diseases, particularly those with multiple treatment modalities. Owing to recent advances in the deciphering of the human genome sequence, high throughput genotyping technology has led to the reduction of the overall costs of genetic testing and allowed the inclusion of genotype-related dosing recommendations into drug package inserts, hence enabling the integration of pharmacogenomics into clinical practice. Although pharmacogenomics gradually assumes an important part in routine clinical practice in developed countries, many countries, particularly from the developing world, still do not have access either to the knowledge or the resources to individualize drug therapy. The PharmacoGenetics for Every Nation Initiative (PGENI) aims to fill this gap, by making pharmacogenomics globally applicable, not only by defining population-specific pharmacogenomic marker frequency profiles but also by formulating country-specific recommendations for drug efficacy and safety. This article aims to highlight the PGENI activities in Europe in an effort to make pharmacogenomics readily applicable in the European healthcare systems, particularly those in developing countries.

Locus-specific database domain and data content analysis: evolution and content maturation toward clinical use.

Genetic variation databases have become indispensable in many areas of health care. In addition, more and more experts are depositing published and unpublished disease-causing variants of particular genes into locus-specific databases (LSDBs). Some of these databases contain such extensive information that they have become known as knowledge bases. Here, we analyzed 1,188 LSDBs and their content for the presence or absence of 44 content criteria related to database features (general presentation, locus-specific information, database structure) and data content (data collection, summary table of variants, database querying). Our analyses revealed that several elements have helped to advance the field and reduce data heterogeneity, such as the development of specialized database management systems and the creation of data querying tools. We also identified a number of deficiencies, namely, the lack of detailed disease and phenotypic descriptions for each genetic variant and links to relevant patient organizations, which, if addressed, would allow LSDBs to better serve the clinical genetics community. We propose a structure, based on LSDBs and closely related repositories (namely, clinical genetics databases), which would contribute to a federated genetic variation browser and also allow the maintenance of variation data.

A1ATVar: a relational database of human SERPINA1 gene variants leading to alpha1-antitrypsin deficiency and application of the VariVis software.

We have developed a relational database of human SERPINA1 gene mutations, leading to alpha(1)-antitrypsin (AAT) deficiency, called A(1)ATVar, which can be accessed over the World Wide Web at www.goldenhelix.org/A1ATVar. Extensive information has been extracted from the literature and converted into a searchable database, including genotype information, clinical phenotype, allelic frequencies for the commonest AAT variant alleles, methods of detection, and references. Mutation summaries are automatically displayed and user-generated queries can be formulated based on fields in the database. A separate module, linked to the FINDbase database for frequencies of inherited disorders allows the user to access allele frequency information for the three most frequent AAT alleles, namely PiM, PiS, and PiZ. The available experimental protocols to detect AAT variant alleles at the protein and DNA levels have been archived in a searchable format. A visualization tool, called VariVis, has been implemented to combine A(1)ATVar variant information with SERPINA1 sequence and annotation data. A direct data submission tool allows registered users to submit data on novel AAT variant alleles as well as experimental protocols to explore SERPINA1 genetic heterogeneity, via a password-protected interface. Database access is free of charge and there are no registration requirements for querying the data. The A(1)ATVar database is the only integrated database on the Internet offering summarized information on AAT allelic variants and could be useful not only for clinical diagnosis and research on AAT deficiency and the SERPINA1 gene, but could also serve as an example for an all-in-one solution for locus-specific database (LSDB) development and curation.

Multi-Omics for Biomarker Discovery and Target Validation in Biofluids for Amyotrophic Lateral Sclerosis Diagnosis.

Amyotrophic lateral sclerosis (ALS) is a rare but usually fatal neurodegenerative disease characterized by motor neuron degeneration in the brain and the spinal cord. Two forms are recognized, the familial that accounts for 5-10% and the sporadic that accounts for the rest. New studies suggest that ALS is a highly heterogeneous disease, and this diversity is a major reason for the lack of successful therapeutic treatments. Indeed, only two drugs (riluzole and edaravone) have been approved that provide a limited improvement in the quality of life. Presently, the diagnosis of ALS is based on clinical examination and lag period from the onset of symptoms to the final diagnosis is ∼12 months. Therefore, the discovery of robust molecular biomarkers that can assist in the diagnosis is of major importance. DNA sequencing to identify pathogenic gene variants can be applied in the cases of familial ALS. However, it is not a routinely used diagnostic procedure and most importantly, it cannot be applied in the diagnosis of sporadic ALS. In this expert review, the current approaches in identification of new ALS biomarkers are discussed. The advent of various multi-omics biotechnology platforms, including miRNomics, proteomics, metabolomics, metallomics, volatolomics, and viromics, has assisted in the identification of new biomarkers. The biofluids are the most preferable material for the analysis of potential biomarkers (such as proteins and cell-free miRNAs), since they are easily obtained. In the near future, the biofluid-based biomarkers will be indispensable to classify different ALS subtypes and understand the molecular heterogeneity of the disease.

Genomic Medicine Without Borders: Which Strategies Should Developing Countries Employ to Invest in Precision Medicine? A New "Fast-Second Winner" Strategy.

Genomic medicine has greatly matured in terms of its technical capabilities, but the diffusion of genomic innovations worldwide faces significant barriers beyond mere access to technology. New global development strategies are sorely needed for biotechnologies such as genomics and their applications toward precision medicine without borders. Moreover, diffusion of genomic medicine globally cannot adhere to a "one-size-fits-all-countries" development strategy, in the same way that drug treatments should be customized. This begs a timely, difficult but crucial question: How should developing countries, and the resource-limited regions of developed countries, invest in genomic medicine? Although a full-scale investment in infrastructure from discovery to the translational implementation of genomic science is ideal, this may not always be feasible in all countries at all times. A simple "transplantation of genomics" from developed to developing countries is unlikely to be feasible. Nor should developing countries be seen as simple recipients and beneficiaries of genomic medicine developed elsewhere because important advances in genomic medicine have materialized in developing countries as well. There are several noteworthy examples of genomic medicine success stories involving resource-limited settings that are contextualized and described in this global genomic medicine innovation analysis. In addition, we outline here a new long-term development strategy for global genomic medicine in a way that recognizes the individual country's pressing public health priorities and disease burdens. We term this approach the "Fast-Second Winner" model of innovation that supports innovation commencing not only "upstream" of discovery science but also "mid-stream," building on emerging highly promising biomarker and diagnostic candidates from the global science discovery pipeline, based on the unique needs of each country. A mid-stream entry into innovation can enhance collective learning from other innovators' mistakes upstream in discovery science and boost the probability of success for translation and implementation when resources are limited. This à la carte model of global innovation and development strategy offers multiple entry points into the global genomics innovation ecosystem for developing countries, whether or not extensive and expensive discovery infrastructures are already in place. Ultimately, broadening our thinking beyond the linear model of innovation will help us to enable the vision and practice of genomics without borders in both developed and resource-limited settings.

Correction: A European Spectrum of Pharmacogenomic Biomarkers: Implications for Clinical Pharmacogenomics.

[This corrects the article DOI: 10.1371/journal.pone.0162866.].

A European Spectrum of Pharmacogenomic Biomarkers: Implications for Clinical Pharmacogenomics.

Pharmacogenomics aims to correlate inter-individual differences of drug efficacy and/or toxicity with the underlying genetic composition, particularly in genes encoding for protein factors and enzymes involved in drug metabolism and transport. In several European populations, particularly in countries with lower income, information related to the prevalence of pharmacogenomic biomarkers is incomplete or lacking. Here, we have implemented the microattribution approach to assess the pharmacogenomic biomarkers allelic spectrum in 18 European populations, mostly from developing European countries, by analyzing 1,931 pharmacogenomics biomarkers in 231 genes. Our data show significant inter-population pharmacogenomic biomarker allele frequency differences, particularly in 7 clinically actionable pharmacogenomic biomarkers in 7 European populations, affecting drug efficacy and/or toxicity of 51 medication treatment modalities. These data also reflect on the differences observed in the prevalence of high-risk genotypes in these populations, as far as common markers in the CYP2C9, CYP2C19, CYP3A5, VKORC1, SLCO1B1 and TPMT pharmacogenes are concerned. Also, our data demonstrate notable differences in predicted genotype-based warfarin dosing among these populations. Our findings can be exploited not only to develop guidelines for medical prioritization, but most importantly to facilitate integration of pharmacogenomics and to support pre-emptive pharmacogenomic testing. This may subsequently contribute towards significant cost-savings in the overall healthcare expenditure in the participating countries, where pharmacogenomics implementation proves to be cost-effective.

Individualizing clozapine and risperidone treatment for schizophrenia patients.

Schizophrenia is a severe disorder that significantly affects the quality of life and total functioning of patients and their caregivers. Clozapine is the first atypical antipsychotic with fewer adverse effects and established efficacy. As a rule of thumb, risperidone is one of the most reliable and effective antipsychotics for newly diagnosed and chronic schizophrenics. Pharmacogenetic studies have identified genomic variants of candidate genes that seem to be important in the way a patient responds to treatment. The recent progress made in pharmacogenomics will improve the quality of treatment, since drug doses will be tailored to the special needs of each patient. In this article, we review the available literature attempting to delineate the role of genomic variations in clozapine and risperidone response in schizophrenic patients of various ethnicities. We conclude that pharmacogenomics for these two drugs is still not ready for implementation in the clinic.

Personalized pharmacogenomics profiling using whole-genome sequencing.

AIM: Pharmacogenomics holds promise to rationalize drug use by minimizing drug toxicity and at the same time increase drug efficacy. There are currently several assays to screen for known pharmacogenomic biomarkers for the most commonly prescribed drugs. However, these genetic screening assays cannot account for other known or novel pharmacogenomic markers. MATERIALS & METHODS: We analyzed whole-genome sequences of 482 unrelated individuals of various ethnic backgrounds to obtain their personalized pharmacogenomics profiles. RESULTS: Bioinformatics analysis revealed 408,964 variants in 231 pharmacogenes, from which 26,807 were residing on exons and proximal regulatory sequences, whereas 16,487 were novel. In silico analyses indicated that 1012 novel pharmacogene-related variants possibly abolish protein function. We have also performed whole-genome sequencing analysis in a seven-member family of Greek origin in an effort to explain the variable response rate to acenocoumarol treatment in two family members. CONCLUSION: Overall, our data demonstrate that whole-genome sequencing, unlike conventional genetic screening methods, is necessary to determine an individual's pharmacogenomics profile in a more comprehensive manner, which, combined with the gradually decreasing whole-genome sequencing costs, would expedite bringing personalized medicine closer to reality.